INHIBITION OF NEUTROPHIL ADHERENCE IMPROVES POSTISCHEMIC VENTRICULAR PERFORMANCE OF THE NEONATAL HEART

Background. Reduction of the leukocyte population during postischemic coronary reperfusion results in decreased neutrophil-mediated tissue i njury. However, the importance of leukocyte adhesion to coronary endot helium for postischemic ventricular dysfunction after global hypotherm ic myocardial ischemia is unknown. Neutrophil integrins (CD11b/CD18) u pregulate in response to cardiopulmonary bypass and ischemic stress, a nd their role in generating postoperative ventricular dysfunction was examined in this study. Methods and Results. An in vivo, in situ model of neonatal cardiac surgery was established in which neutrophil adher ence was manipulated by administering NPC 15669 (an inhibitor of neutr ophil CD11b/CD18 surface receptor upregulation). Seventeen 3- to 5-day -old piglets (8 controls and 9 NPC 15669-treated animals) were instrum ented with a coronary sinus catheter, sonomicrometry crystals across t he short axis of the left ventricle (LV), and a micromanometer positio ned in the LV. Hearts were subjected to 90 minutes of hypothermic isch emia after a single dose of cold crystalloid cardioplegia. Myocardial granulocyte accumulation during ischemia and reperfusion was reduced i n NPC animals compared with controls (myeloperoxidase activity, 43.4+/ -2.6 and 75.8+/-6.3 mumol/10 mg tissue, respectively; P less-than-or-e qual-to .005). This was associated with a reduction in coronary vascul ar resistance in NPC animals compared with controls (P less-than-or-eq ual-to .02) and decreased release of myocardial creatine phosphokinase throughout reperfusion (P less-than-or-equal-to .05). NPC animals dem onstrated an improved preservation of the end-systolic pressure-volume relation after discontinuation of cardiopulmonary bypass (71+/-6% and 96+/-6% at 60 minutes, respectively; P less-than-or-equal-to .05). Th ere was no difference in ventricular compliance between groups. Conclu sions. These data demonstrate that inhibition of neutrophil CD11b/CD18 surface adherence receptor upregulation reduces granulocyte accumulat ion in myocardium after hypothermic global ischemia, reduces myocyte d amage, and improves ventricular systolic function.